According to the adenosine hypothesis, a reduction in myocardial O2 tension produced by inadequate coronary blood flow, hypoxemia, or increased metabolic activity of the heart leads to release of adenosine from the myocardium. Adenosine enters the interstitial fluid space to reach the coronary resistance vessels and induces vasodilation by activating adenosine receptors. However, it cannot be responsible for the increased coronary flow observed during prolonged enhancement of cardiac metabolic activity because release of adenosine from cardiac muscle is transitory. Factors that alter coronary vascular resistance are illustrated in
Fig. 17.35
Effects of Diminished Coronary Blood Flow
Most of the O2 in coronary arterial blood is extracted during one passage through the myocardial capillaries. Thus the supply of O2 to myocardial cells is flow limited; any substantial reduction in coronary blood flow curtails O2 delivery to the myocardium because O2 extraction is nearly maximal even when blood flow is normal.
A reduction in coronary flow that is neither too prolonged nor too severe to induce myocardial necrosis can nonetheless cause substantial (but temporary) dysfunction of the heart. A relatively brief period of severe ischemia followed by reperfusion can result in pronounced mechanical dysfunction (myocardial stunning). However, the heart eventually recovers fully from the dysfunction. The pathophysiological basis for myocardial stunning appears to be intracellular Ca++ overload, initiated during the period of ischemia, combined with the generation of OH− and superoxide free radicals early in the period of reperfusion. These changes impair the responsiveness of myofilaments to Ca++ .
In the normal human heart, there are virtually no functional intercoronary channels. Abrupt occlusion of a coronary artery or one of its branches leads to ischemic necrosis and eventual fibrosis of the areas of myocardium supplied by the occluded vessel. However, if a coronary artery narrows slowly and progressively over a period of days or weeks, collateral vessels develop and may furnish sufficient blood to the ischemic myocardium to prevent or reduce the extent of necrosis. Collateral vessels may develop between branches of occluded and nonoccluded arteries. They originate from preexisting small vessels that undergo proliferative changes of the endothelium and smooth muscle. These changes may occur in response to wall stress and to chemical agents, including vascular endothelial growth factors (VEGFs) released by the ischemic tissue. The VEGFs, of which there are at least five in mammals, are glycoproteins. The VEGFs induce angiogenesis, elicit vasodilation and increase endothelial permeability. By causing vasodilation, VEGFs enable perfusion of more capillaries and increase capillary permeability by opening tight junctions between endothelial cells and by adding fenestrations.
Myocardial stunning, prolongedventriculardysfunctionwithoutmyocardialnecrosis,maybeevidentinpatientswhohavesufferedanacutecoronaryarteryocclusion.Ifthepatientistreatedsufficientlyearlybycoronarybypasssurgeryorballoonangioplasty,andifadequatebloodflowisrestoredtotheischemicregion,themyocardialcellsinthisregionmayrecoverfully.However,formanydaysorevenweeks,thecontractilityofthemyocardiumintheaffectedregionmaybegrosslysubnormal.